The central question addressed in our studies is whether a low nutritional status of essential fatty acids increases the predisposition to psychiatric disorders including depression and schizophrenia or to pathological behaviors such as homicide and suicide. Some essential fatty acids, in particular docosahexaenoic acid (DHA), are selectively concentrated in the brain, but these nutrients are ultimately available only from dietary sources e.g. seafood, which is rich in this omega-3 fatty acid. Our projects have examined these questions from several perspectives: population comparisons in epidemiological studies, clinical interventional studies in adults with psychiatric disorders, and observational studies of the relationship of essential fatty acids status to the function of key neurotransmitter systems, which may help to elucidate mechanism of action. In addition to the status of adults, nutritional inadequacies both in early development may also contribute to an increased predisposition toward psychiatric disorders or abnormal behaviors. Thus, we have also conducted two developmental outcome studies. 1) a four decade follow-up study examined the maternal essential fatty acid status at time of birth and the lifetime risk of developing schizophrenia. 2) An intervention study which examined the effects of supplementing infant formulas with DHA and arachidonic acid (AA) on the short and long term consequences to neurological development among rhesus monkeys. The cross-national ecological studies which have compared the rates of seafood consumption to prevalence rates of psychiatric disorders indicate that there may be a specific relationship to prevalence rates of affective and impulsive disorders, but not to schizophrenia. In a prior study we reported that seafood consumption predicted lower prevalence rates of major depression (r = -0.84, p< 0.0005) over a nearly 60-fold range across countries. Consistent with this report we found that bipolar spectrum disorders (manic depressive disorders) have a well defined relationship to seafood consumption with an apparent threshold of approximately 75 lbs/person/y. We conducted each of these studies using data from the gold standard of psychiatric epidemiological studies, the Epidemiological Catchment Area Study. Two studies within countries yielded similar results. 1) We studied a population of 1,767 subjects within Northern Finland and found that subjects who consumed fish twice a week or more were at lower risk of reporting depressive symptoms (odds ratio 0.63) and suicidal thinking (odds ratio 0.57), compared to infrequent fish consumers. The subjects who consumed vegetable oils were more than twice as likely to report being depressed compared to those with no consumption. This is significant because vegetable oils are high in omega-6 fatty acids which compete with the effects of omega-3 fatty acids. 2) We again found similar results among a community sample of 200 elderly subjects that represented 80% of the elderly people in two counties in Iowa. Low plasma concentrations of plasma DHA alone significantly predicted more severe sleep complaints and reports of anxiety and predicted depression among women.A series of three studies done by our group has indicated that there is no relationship between essential fatty acid status and schizophrenia. 1) Across 14 countries, there was no significant relationship between prevalence rates of schizophrenia and seafood consumption using Epidemiological Catchment Area data. 2) These cross-national data are consistent with the results of a double-blind, placebo-controlled multi-center trial we conducted among 74 chronic schizophrenics (In collaboration with the Stanley Foundation). No clinical improvements were found comparing consuming supplements of 3 g/d of EPA to 3 g/d of mineral oil, for 4 months. 3) We examined the essential fatty acid composition of maternal plasma drawn on the day of birth comparing 51 control mothers to mothers of 27 children that developed psychosis over the next four decades. In contrast to the predicted hypothesis, the mothers of children who developed psychosis were not deficient in any essential fatty acid. In summary, these data suggest that there could be a specific relationship of seafood consumption and omega-3 status to prevalence rates of affective and impulsive disorders, but not to the prevalence of schizophrenia. Three studies indicate that inadequate omega-3 fatty acid consumption may contribute to an increased risk of mortality from suicide and homicide. 1) Across 31 countries, greater seafood consumption predicts a lower risk of death due to suicide. 2) Among suicide attempters, low concentrations of the omega-3 fatty acid, eicosapentaenoic acid (EPA), alone were robustly correlated with greater psychopathology scores. 3) Finally, in a cross-national analysis, higher homicide mortality rates correlated with lower rates of seafood consumption across 26 countries in a cross-national analysis (r= - 0.63, p< 0.0005).One of the most well replicated findings in biological psychiatry is that suicide is associated with low concentrations of a marker of central serotonin concentrations called CSF 5-HIAA. Regulating central serotonin concentrations is also the cornerstone of pharmacological therapy for major depression. Thus we predicted, and found, that low plasma concentrations of omega-3 fatty acids predicted low concentrations of CSF 5-HIAA in healthy control subjects and late onset alcoholics, higher concentrations of plasma DHA predicted higher concentrations of CSF 5-HIAA. We also replicated this finding among 104 adult rhesus monkeys finding again that higher concentrations of the omega-3 fatty acids in plasma predicted higher concentrations of CSF 5-HIAA. Among these animals, higher EPA and DHA concentrations in plasma also predicted more functional dominance behaviors. These findings also suggest that omega-3 fatty acids may modulate impulsive behaviors through regulation of the serotonergic nervous system. The basic mechanisms by which essential fatty acid status might regulate serotonergic function merits further exploration.We have begun to examine if these disorders are, in part, a long-term consequence of a nutritional deficiency during early development. In prior experiments, it has been established that separating rhesus infants from their mothers at birth and raising them in a nursery imparts a lifetime predisposition toward abnormal and aggressive behaviors. We noted that while in the nursery the infants are fed formulas that are virtually devoid of DHA and AA, which is similar to human formulas in this country. Thus, we compared two groups of infant rhesus monkeys that were removed from their mothers at birth and were raised in a stringently controlled nursery for the first six months. One group received standard infant formula while the other group received formulas supplemented with AA (0.8%) and DHA (0.8%), a composition similar to the milk of rhesus monkey mothers. DHA/AA fed infants had profoundly improved motor development and visual orientation scores in as little as seven days. The heart rate variability, a measure of central nervous system function, remained improved in adolescence up to 3.5 years after the dietary intervention had stopped, indicating an enduring developmental effect. CSF 5-HIAA was decreased in the DHA/AA group, but only during the six months of formula feeding. We cannot determine directly whether the supplementation raised or lowered the brain concentrations of serotonin among these infants. However, the behavioral and physiological improvements noted above, were consistent with improved serotinergic function.